(1) Field of the Invention
The present invention relates to novel hydroxy substituted anthraquinones and to processes for preparing these compounds. The anthraquinones can also be methoxy substituted in place of hydroxyl groups. These compounds are particularly useful in treatments for malaria, schistosomiasis and elephantiasis (filariasis) helminthic and other parasitic diseases. Certain novel anthraquinones are described.
(2) Description of Related Art
There are many parasitic diseases. Lymphatic filariasis (elephantiasis) in particular is a devastating disease caused by Wuchereria bancrofti and Brugia malayi spp. The World Health Organization estimates that 120 million people globally are affected and at least 40 million are disabled both physically and psychosocially. This is one of the major public health problems with socioeconomic impacts in Africa, Asia, the Western Pacific and the Americas (Ottesen, E. A., Trop. Med. Int. Hlth. 5, 591-594 (2000)). About 90% of these infections are caused by Wuchereria bancrofti, and the remainder by Brugia spp. Humans are the only host for W. bancrofti (Anonymous, The Global Alliance for the Elimination of lymphatic Filariasis—epidemiology. Http://www.filariasis.org /2002)).
Numerous quinones including dihydroxy- and trihydroxyanthraquinones are widely distributed in plant kingdom and contribute to pigmentation in plants (Thomson, R. H., Naturally Occurring Quinonones, Academic press, pp 367-535, London (1971)). Hemerocallis fulva kwanza kaempfer (daylily) roots was reported to contain several anthraquinone derivatives, naphthaline glycosides and flavones (Cichewicz, R. H., et al., Tetrahedron 58, 8597-8606 (2002)). In our earlier studies, some of the anthraquinones isolated from daylily roots were found to be active against Schistosoma mansoni, one of the Schistosoma spp. parasites responsible for schistosomiasis (Cichewicz, R. H., et al., Tetrahedron 58 8597-8606 (2002)). Schistosomiasis is also a debilitating disease caused by parasitic trematodes of the genus Schistosoma that afflicts 200 million people worldwide. These active anthraquinones from daylily roots were assayed against filarial parasite (Brugia malayi) and were found to, be active. The presence of these active anthraquinones in daylily roots is very small.
It is also essential to explore the possible utility of these active and anthraquinone analogues as prophylactic and/or therapeutic agent for parasitic diseases. Therefore, it is a necessity to synthesize these anthraquinones to further evaluate their efficacy in vivo and determine the toxicity in order to determine their potential as therapeutic drugs for filariasis and schistosomiasis.
The production of anthraquinones was reported by the catalytic oxidation of anthracene obtained from coal tar (Nanba, Y., et al., U.S. Pat. No. 3,870,655; 1975; and Rodriguez, F., et al., Separation Science and Technology 24 275-289 1989). It has also been prepared by Diels-Alder cyclo-addition and Friedel-Crafts acylation reactions using suitable reagents. The Diels-Alder reaction between 1,4-napthaquinone and 1,3-diene followed by dehydrogenation of the resulting tricyclic adduct yielded anthraquinones (Boisvert, L., J. Org. Chem. 53 4052-4059 (1988)). However, production of 1,4-naphthaquinone and 1,3-dienes are complex and costly.
The Friedel-Crafts acylation reaction is one of the most commonly used reactions in synthetic organic chemistry, which is catalyzed by Lewis acids such as AlCl3, BF3, FeCl3, TiCl4 and Sc(OTf)3 (Olah, G. A., Friedel-Crafts and related reactions, Wiley Interscience, NY, Vol II, part I (1964); Bensari, A., et al., Synthesis 267-271 (2003); Kotsuki, H., et al., Synthesis 603-606 (1999); and Kobayashi, S., Eur. J. Org. Chem. 15-27 (1999)). The mechanism involves the formation of an acylium ion intermediate that are generated by the reaction between carboxylic acid derivatives and the acid catalyst.
Another method for the preparation of anthraquinones was reported by the condensation of phthalic anhydride and benzene using an equimolecular amount of HF and BF3 as catalysts. The resulting o-benzoylbenzoic acid was then converted to corresponding anthraquinone by heating it with concentrated sulfuric acid or other means of cyclisation. The drawbacks of this method included were the purification of o-benzoylbenzoic acid from crude reaction mixture, poor yield and the formation of sulfonated products (Devic, M., U.S. Pat. No. 4,379,092 (1983)). In order to avoid these disadvantages, the reaction was attempted under gaseous phase over a solid catalyst such as silico-aluminate (Yang, P., et al., Huaxue Shijie 34 258-260 (1993)) or titanium oxide Akazawa, Y., JP 61100543 (1986)). However, these processes required high temperature and expensive installations.